Implementing genomic medicine in clinical care of deaf patients

在聋哑患者的临床护理中实施基因组医学

基本信息

批准号：
9974998
负责人：
XUE Z LIU
金额：
$ 63.81万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-08 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974998
关键词：
Address Adult Animal Model Area Attitude Basic Science Behavior Biology CRISPR/Cas technology Candidate Disease Gene Caring Cell Therapy Cells Child Clinic Clinical Clinical assessments Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Data Databases Diagnosis Diagnostic Electrophysiology (science)Etiology Family Feasibility Studies Foundations Gene Expression Profiling Genes Genetic Genetic Counseling Genome Genomic approach Genomic medicine Genomics Genotype Grant Hair Cells Health Status Hearing Human Individual Infrastructure International Knock-in Mouse Knowledge Laboratories Labyrinth Language Development Mediating Medical Medical Records Minority Modeling Molecular Mus Mutation Nucleic Acids Outcome Participant Patient Care Patients Phenotype Physiology Population Procedures Proteins Protocols documentation Quality of Care Recovery of Function Role Sampling Speech Development Surveys Testing Therapeutic Therapeutic Intervention Therapeutic Studies Translating Universities Variant accurate diagnosis base bioinformatics pipeline causal variant clinical care clinical database clinical practice cohort cost effectiveness database of Genotypes and Phenotypes deaf deafness exome experimental study functional genomics gene discovery gene therapy genetic deafness genetic variant genome editing genome sequencing genomic data genomic profiles genomic tools genomic variation hearing impairment hearing restoration hearing screening improved in vivo induced pluripotent stem cell innovation insight next generation sequence data normal hearing novel novel therapeutics phenotypic data pre-clinical precision medicine preclinical study progenitor repository research clinical testing screening screening program tool variant detection

项目摘要

Abstract: This continuing proposal will translate basic research utilizing high-throughput genomic approaches and functional genomics into routine diagnostic and therapeutic tools for non-syndromic hearing loss (NSHL), the most common type of hearing impairment in children and adults. We have developed a genomic variant detection platform MiamiOtogenomics - composed of MiamiCapitalArray/MiamiOtoGenes panels/exome (WES)/genome (WGS) and developed a genotype and phenotype database – MiamiGeneHeal. As shown in the preliminary data, we have already collected approximately 3,000 DNA samples with phenotypic data from a large international cohort (Miami Otogenetic Repository) of families with NSHL. Moreover, we have excluded all known HL genes in over 200 families, successfully identified more than 18 potential new candidate genes, created animal models for human HL, and have generated human iPSCs from patients with genetic deafness. We will build on these accomplishments and preliminary data by proposing to complete the following specific aims: 1. Apply an innovative genomics-based MiamiOtogenomics pipeline for NSHL; 2. Identify factors influencing the decision to pursue and act on genomic testing; 3. Initiate preclinical therapeutic experiments as a proof-of-concept for potential treatments for HL. The foundation of the proposal will leverage the exceptional genomics capacity of collaborators at the University of Miami into a genomic-based, minority-focused, diagnostic and treatment pipeline for HL. The overarching purpose of this application is to transit discoveries made in laboratory to patient care. This study will translate genomic analysis into clinical hearing screening to elucidate the exact molecular etiology for HL, which will enable more accurate diagnoses, better quality of care, more effective genetic counseling, as well as improved cost-effectiveness in medical care. In addition, we expect to contribute significantly to genotype-phenotype studies and to establish a robust framework for assessing long-term clinical outcomes. Moreover, this study will contribute to our fundamental understanding of HL. Finally, our innovative preclinical therapeutic experiments in our knockin mouse and human iPSC models using CRISPR will potentially discover new treatments for HL. This study will inform two important clinical aspects of precision medicine in USA populations, especially in USA minorities: general acceptance in clinical practice and clinical utility. We will perform one of the largest and most integrated clinical/genomic/functional/novel therapeutic studies on NSHL to date. Our prior results, the interdisciplinary team's expertise and our established study infrastructure and population access support feasibility of our Aims.

摘要：这项持续提案将利用高通量基因组方法转化基础研究，并将功能基因组学纳入非综合征性听力损失（NSHL）的常规诊断和治疗工具中，这是最常见的我们开发了一个基因组变异检测平台。 MiamiOtogenomics - 由 MiamiCapitalArray/MiamiOtoGenes panel/外显子组 (WES)/基因组 (WGS) 和开发了一个基因型和表型数据库——MiamiGeneHeal，如初步数据所示，我们已经有了。从大型国际队列中收集了大约 3,000 个带有表型数据的 DNA 样本（迈阿密 Otogene 此外，我们还成功排除了 200 多个家族中所有已知的 HL 基因鉴定了超过 18 个潜在的新候选基因，创建了人类 HL 动物模型，并产生了人类我们将在这些成就和初步数据的基础上，提出以下建议：完成以下具体目标： 1. 将基于基因组学的创新型 MiamiOtogenomics 流程应用于 NSHL；确定影响基因组测试决定和采取行动的因素；3.启动临床前治疗实验；作为 HL 潜在治疗方法的概念验证该提案的基础将利用特殊的基因组学。迈阿密大学合作者进行基于基因组、以少数族裔为重点的诊断和治疗的能力该应用程序的首要目的是将实验室的发现转移到患者护理中。研究将基因组分析转化为临床听力筛查，以阐明 HL 的确切分子病因学，这将实现更准确的诊断、更好的护理质量、更有效的遗传咨询以及改进的此外，我们期望为基因型-表型研究和研究做出重大贡献。此外，这项研究将有助于我们建立一个强有力的框架来评估长期临床结果。最后，我们在敲入小鼠中进行了创新的临床前治疗实验。使用 CRISPR 的人类 iPSC 模型将有可能发现 HL 的新疗法。这项研究将提供两个重要信息。精准医疗在美国人群中的临床方面，尤其是美国少数族裔：临床普遍接受我们将进行最大且最综合的临床/基因组/功能/新颖之一。我们迄今为止对 NSHL 的治疗研究、跨学科团队的专业知识和我们既定的研究。基础设施和人口准入支持我们目标的可行性。